The present invention relates to compositions and a method for treating a patient having cancer. More specifically, the present invention is directed to novel indenoisoquinoline derivatives and to their use in cancer therapy.
The control and cure of cancer represents one of our most challenging health problems. The treatment of cancer can be approached by several modes of therapy including surgery radiation, chemotherapy or a combination of any of these treatments. Chemotherapy continues to be an indispensable therapy for inoperable or metastatic forms of the disease. Thus, the discovery of compounds specifically targeting cancer cells, or the cellular mechanisms involved in the proliferation of cancer cells, can provide significant advancement in the eradication or control of cancer.
The selection of compounds having effective anticancer activity is complicated by the still limited knowledge of cancer cell biology and biochemistry. Therefore, development of new effective anti-cancer agents remains heavily dependent on screening of new compounds for cytotoxic activity. Antineoplastic drug candidates exhibit enhanced cytotoxicity against cancer cells relative to normal cells. Methods of screening for anticancer activity have focused on several targets: (1) the ability of a compound to inhibit tumor growth and/or progression in animal studies; (2) inhibition of cell growth/proliferation in cell lines of cancerous origin; and (3) inhibition of intracellular processes necessary for the growth or propagation of cancer cells.
The mouse L1210 leukemia cell line was initially the preferred model system used for screening compounds for anti-cancer activity. However, the P388 murine leukemia system was found to be more sensitive and predictive than L1210
The mouse L1210 leukemia cell line was initially the preferred model system used for screening compounds for anti-cancer activity. However, the P388 murine leukemia system was found to be more sensitive and predictive than L1210 leukemia system; it has been used as a primary screen during the past decade. Systematic screening for compounds exhibiting toxicity to these two cell lines has resulted in the isolation of a large number of active natural products. However, the anticancer activities of these compounds were predominantly for leukemia, lymphoma and a few rare tumors. Low clinical efficacy, or the lack of clinical efficacy of known chemotherapeutics against slower growing solid tumors, is aserious concern.
Considering the diversity of cancer in terms of cell type, morphology, growth rate and other cellular characteristics, the U.S. National Cancer Institute (NCI) has developed a xe2x80x9cdisease-orientedxe2x80x9d approach to anticancer activity screening (M. R. Boyd, in xe2x80x9cPrinciple of Practice of Oncologyxe2x80x9d J. T. Devita, S. Hellman, S. A. Rosenberg (Eds.) Vol. 3, PPO Update, No. 10, 1989). This in vitro prescreening system is based on the measurement of anticancer cytotoxicity against human cancer cell line panels consisting of approximately 60 cell lines of major human cancers (including leukemia and slower growing tumor cells such as lung, colon, breast, skin, kidney, etc.) and is referred hereinafter as xe2x80x9cCOMPARExe2x80x9d screening. An important advantage of the new in vitro screening panels is the opportunity to facilitate identification of compounds that are selectively more cytotoxic to cells of certain types of cancers, thus increasing the ability to select compounds for further study with respect to specific diseases.
The compounds of the present invention were screened for antineoplastic activity using the COMPARE screening methodology. The results demonstrate that the compounds are antineoplastic agents for use in treating human cancers.
Anticancer agents are known to act through a variety of mechanisms to destroy or inhibit the proliferation of cancer cells. For example, some agents are antimetabolites which act as false substrates in the biochemical processes of cancer cells. One compound which has this mechanism of action is methotrexate, an analog of folic acid, which functions in part by binding to dihydrofolate reductase, thereby preventing the formation of guanine and adenine from the folic acid precursor molecule. Thus, methotrexate inhibits the ability of cancer cells to construct DNA by inhibiting the proper metabolism of folic acid.
Other anticancer agents act by alkylating DNA strands, thereby producing defects in the normal double helical structure of the DNA molecule. This alkylation may cause the formation of breaks and inappropriate links between (or within) strands of DNA. Such disruption of the DNA structure, if not repaired by intracellular repair mechanisms, impairs the cell""s ability to replicate it""s DNA. Examples of alkylating anticancer agents are cyclophosphamide and chlorambucil.
Some anticancer agents target the intracellular mechanisms involved in replication of the DNA strand itself. Replication of a cell""s genetic material requires a means to pull the DNA double helix apart into two strands. This separation is typically accomplished by the enzyme topoisomerase I. Disruption of the function of this enzyme results in DNA strand breaks in cells that are dividing, thereby causing the death of the dividing cell. Because cancer cells grow and reproduce at a much faster rate than normal cells, they are more vulnerable to topoisomerase inhibition than are normal cells. Thus, agents that inhibit topoisomerase I are known to be potent anticancer agents. The drug camptothecin was shown to be an inhibitor of topoisomerase I and a potent anticancer agent; unfortunately, camptothecin also produced toxic side effects. The search for potent inhibitors of topoisomerase I with lessened toxicity to normal cells continues.
Many of the compounds of the present invention caused inhibition of topoisomerase I, to varying extents. Therefore, it appears that some of the growth inhibition demonstrated through COMPARE testing occurs through this mechanism of action. However, several of the indenoisoquinolines of the present invention were surprisingly potent cell growth inhibitors even though their inhibitory effects on topoisomerase I were relatively small in comparison to other agents tested. These data demonstrate that the novel indenoisoquinolines of the present invention cause inhibition of cell growth, at least in part, through another mechanism of action besides inhibition of topoisomerase I. The present invention describes novel indenoisoquinoline compounds, many of which are potent inhibitors of topoisomerase I, and are useful as anticancer agents. Further, the present invention describes novel indenoisoquinoline compounds which are potent inhibitors of cell growth, and are thus potent anticancer agents.